The research theme of the Indiana Alcohol Research Center (IARC) is Genetic Determinants of Alcohol Ingestion. We hypothesize that between- individual variability in response to ethanol, much of which being genetic, is an underlying factor of individual differences in ethanol ingestive behavior and susceptibility to alcoholism. The IARC has unique resources to pursue this kind of research. A team of investigators with broad-based expertise will address this theme in experimental animals and humans. Research for the 4 core, 5 research, and a pilot projects components are proposed: a) the association of human alcohol and aldehyde dehydrogenase polymorphisms to alcoholism and its complications; b) the heritability, sensitivity and repeatability of a variety of responses to ethanol (e.g., subjective sensations, electroencephalogram, event-related potential, eye-movements, memory, and motor coordination and speed), c) the effects of recent drinking history on these measures; d) the study of neurotransmitter systems implicated in abnormal alcohol-seeking behavior and alcohol tolerance in rats; and e) selective breeding for alcohol- preference in mice. The human studies will employ subjects who are positive and negative for family history of alcoholism, and monozygotic twin pairs and siblings who are discordant in risk-relevant personality/temperament (in particular, disinhibition and impulsivity) dimensions, with both oral ethanol challenge and an intravenous constant- ethanol-concentration clamping technique. The animal studies will use rat lines selectively bred for alcohol preference and non-preference. Core laboratory functions will include the production of selective bred high and low alcohol-preferring rats for research, the search for candidate genes and quantitative trait loci relevant to alcohol drinking behavior, and support of research into the structure-function relationships of molecules important to alcohol metabolism and the actions of ethanol.